Between Bedside and Bench in 2011

Chemotherapy can save the lives of many individuals with cancer. Unfortunately, it usually causes infertility after treatment, posing a concern for these people who will face a lifetime condition that considerably limits the quality of their lives. Advances in the field of oncofertility have brought hope to cancer survivors who long to plan a family; however, standard approaches only rely on cryopreservation of sperms and eggs before treatment and do not prevent infertility. In 'Bedside to Bench', Min Xu, Mary Ellen Pavone and Teresa Woodruff examine a study where individuals treated with gonadotropin-releasing hormone (GnRH) agonists before cancer therapy showed a decreased risk of infertility. How these agonists work to suppress and protect ovarian function and increase fertility in women after treatment is still unclear and begs further investigation at the bench. In 'Bench to Bedside', Amander Clark, Bart Phillips and Kyle Orwig discuss potential experimental options to preserve and restore male fertility after chemotherapy. These approaches will shed light into mechanisms of male fertility and spermatogenesis and may be the alternative to sperm freezing, which is not suitable for prepubertal boys and men unable to make sperm.

The complexity of the brain adds another level of difficulty to our understanding of how the brain develops, matures and functions. Both structural and molecular components define brain functional connectivity, and its alteration may result in developmental, behavioral and social deficits. Uncovering the roots and mechanisms behind neurodevelopmental disorders, such as fragile X syndrome or autism, is the goal of several lines of research. Despite the challenges associated with studying these diseases, new advances are linking pathological genetic changes with mechanisms in the brain. In Bench to Bedside, Guoping Feng and Jonathan Ting peruse a study that uncovers how fragile X syndrome–causing gene mutations unleash a translation break that finally leads to overexpression of synaptic proteins that alter the proper transmission of signals at the synapse. Furthermore, changes in the brain during the development of a person can also provide information about when and where the diseased brain loses functional connectivity. In Bedside to Bench, Jeffrey Neul proposes that studying the functional networks in people with autism and other neurodevelopmental disorders, and correlating changes with functional connectivity in animal models of these diseases, will uncover the mechanisms of normal and abnormal development and suggest possible treatment strategies.

Despite remarkable advances in managing disease progression in people infected with HIV, an effective vaccine to prevent infectivity and stop the HIV epidemic remains an unmet clinical need. The genetic variability of the virus and the poor natural immune response—humoral and cellular—generated against HIV are hurdles that pose challenges to vaccine development. In 'Bench to Bedside', Bruce Walker, Rafi Ahmed and Stanley Plotkin examine a study in rhesus macaques where a vector-based viral vaccine that elicits a persistent and rapid T effector cell response to SIV antigens results in control of the infection. Although only 50% of the rhesus macaques controlled the infection, this in vivo finding stresses how outdoing the natural immune cellular response can prove effective to clear systemic viruses. But a humoral response will still remain the 'holy grail' to avoid HIV infection and transmission. In 'Bedside to Bench' Tom Hope peruses recent vaccine trials to propose how to best achieve an effective antibody response against HIV by discussing the perks and perils of non-neutralizing versus broadly neutralizing antibodies.

Autoimmunity develops when one's own immune cells and pathogenic antibodies react against the body, causing inflammation, degeneration, tissue destruction and even organ failure. But autoimmunity mediators can also evoke other pathological side effects, and individual factors can worsen the morbidity of the people suffering from autoimmune disorders, adding another level of complexity to these diseases. In 'Bedside to Bench', Mark Anderson and Michael Waterfield peruse a potential link between immunodeficiency and autoimmunity. Autoantibodies against cytokines involved in tackling Candida albicans infection may underlie the trait of increased susceptibility to yeast observed in people with such autoantibodies. In 'Bench to Bedside', Daniel Cua and Jonathan Sherlock discuss how the immune response induced by gut microbiota may be responsible for autoimmune attacks at distant sites, such as the joints.

Genetic mutations can cause numerous diseases. These alterations affect not only protein-coding genes but also regions that were until recently thought to be trivial in disease. In 'Bedside to Bench', David Salzman and Joanne Weidhaas examine a human study showing how a silent mutation impairs the binding of miR-196, increasing the risk for Crohn's disease. Therefore, alterations of miRNA target sites as pathogenic mechanism begs further investigation. miRNAs themselves can also be the root of disease. In 'Bench to Bedside', Carlo Croce peruses a study in vivo showing evidence of tumor addiction to miR-21 in a mouse model of cancer, which highlights the role of miRNAs as initiators of disease. Targeting these drivers will help to develop effective drugs.

Atherosclerotic lesions can result in fatal cardiovascular disease, but what triggers the formation of the atheroma plaques and their progression still begs further investigation. In 'Bench to Bedside', Göran K Hansson and Lars Klareskog peruse how the NLRP3 inflammasome can be activated by cholesterol crystals and worsen atherosclerosis by triggering inflammation through the release of IL-1β from macrophages. But these cells can also die at the lesion site, forming a necrotic core in the atheroma by building up apoptotic cells and debris. In 'Bedside to Bench', Ira Tabas discusses a human study showing that lesional necrosis along with thinning of the fibrotic cap are predictive of culprit lesions involved in fatal disease. Understanding the molecular underpinnings of these two morphological features may lead to new therapies to prevent or decrease the risk for major cardiovascular disease.

Animal experiments using single organs as models of fibrosis spur therapeutic development toward promising targets, but testing of these therapies in human fibrosis yielded disappointing results and limited efficacy. Finding core pathways relevant in different organs that can become fibrotic will uncover molecules that will prove useful as therapeutic targets in many species, including humans. In 'Bench to Bedside', Scott Friedman, Wajahat Mehal and John Iredale discuss this new paradigm in fibrosis research and its potential as a new drug development approach. In 'Bedside to Bench', Alison Eddy peruses how the protein encoded by UMOD, a gene linked to variable risk for chronic kidney disease and hypertension in humans, may have a role in fibrosis and kidney disease. Uncovering the normal function of UMOD and its gene variants will shed light on the pathogenesis of chronic kidney disease and aid in the discovery of new targets for kidney fibrosis and hypertension.

Bone is an endocrine organ that reaches out to other tissues, orchestrating responses that may have a role in pathology and physiology at distant sites. In 'Bench to Bedside', L. Darryl Quarles discusses recent studies showing how a feedback loop between the bone hormone FGF-23 and renal phosphate excretion and vitamin D metabolism is integrated with the classical PTH–vitamin D axis in chronic kidney disease (CKD). This new paradigm may change the diagnosis and treatment of disordered mineral homeostasis of people with CKD. A recent epidemiological study argues a mechanistic link between bone loss and atherosclerosis, maladies usually linked to aging. In 'Bedside to Bench', Sundeep Khosla discusses how this clinical study underpins research showing that mediators of inflammation and oxidative stress share common mechanisms that may lead to this calcium shift during aging.

Finding mechanisms of viral resistance and new ways to tackle chronic hepatitis will help find a cure for this disease. In 'Bench to Bedside', Christopher Walker and Benoît Callendret highlight studies showing that overcoming immune exhaustion during chronic infection by blocking several inhibitory pathways of T cells may restore an adequate immune response. In 'Bedside to Bench', Lawrence Corey, Joshua Schiffer and John Scott discuss recent advances in antiviral therapy with protease inhibitors and the findings of a mathematical model that predicts possible single and double mutations prior to antiviral therapy.

Infection with methicillin-resistant Staphylococcus aureus (MRSA) can cause symptoms ranging from mild skin infections to more severe disease in various organs, even among healthy individuals. The ability of this pathogen to escape our immune arsenal and overcome antibiotic therapy poses a challenge to preventing their spread and treating the related symptoms. In 'Bench to Bedside', Scott Kobayashi and Frank DeLeo explore new approaches for vaccine development that focus on antigens required for establishment of disease. Studies with infected mice immunized against S. aureus coagulases—important for abscess formation and bloodstream infection—suggest such an approach may be used to reduce bacterial load and protect against severe disease in humans. In 'Bedside to Bench', Michael Otto examines a large human study where the presence of genes encoding Panton-Valentine leukocidin toxin (PVL) in community-associated MRSA did not correlate with complicated skin structure infections—a result opposing the widespread notion that PVL is the primary CA-MRSA virulence factor.